| Summary: | α-Synuclein (αS) is an amyloidogenic neuronal protein associated with several neurodegenerative disorders. Although unstructured in solution, αS forms α-helices in the presence of negatively charged lipid surfaces. Moreover, αS was shown to interact with FAs in a manner that promotes protein aggregation. Here, we investigate whether αS has specific FA binding site(s) similar to fatty acid binding proteins (FABPs), such as the intracellular FABPs. Our NMR experiments reveal that FA addition results in i) the simultaneous loss of αS signal in both 1H and 13C spectra and ii) the appearance of a very broad FA 13C-carboxyl signal. These data exclude high-affinity binding of FA molecules to specific αS sites, as in FABPs. One possible mode of binding was revealed by electron microscopy studies of oleic acid bilayers at pH 7.8; these high-molecular-weight FA aggregates possess a net negative surface charge because they contain FA anions, and they were easily disrupted to form smaller particles in the presence of αS, indicating a direct protein-lipid interaction. We conclude that αS is not likely to act as an intracellular FA carrier. Binding to negatively charged membranes, however, appears to be an intrinsic property of αS that is most likely related to its physiological role(s) in the cell.
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